The two reasons most often given for the generally poor functional outcomes observed after peripheral nervous system (PNS) injury are that regenerating axons in peripheral nerves grow slowly and that muscles are often reinnervated by functionally inappropriate motoneurons. Electrical stimulation (ES) of the cut nerve at the time of its surgical repair promotes a significant enhancement of the growth of regenerating axons that is mediated by neuronal neurotrophins. However, there are many circumstances in which ES could be used and ES also results in an increase in muscle reinnervation by functionally inappropriate motoneurons. Exercise promotes BDNF expression in the brain and spinal cord and this could result in a stimulation of the growth of regenerating axons. The goal of this project is to compare the effects of one form of exercise, treadmill training, to those of ES on axon regeneration in peripheral nerves. A combination of transgenic and knockout mice will be used as a novel model system to investigate whether an exercise- induced enhancement of the growth of regenerating axons is mediated by neuronal neurotrophins. By comparing the effects of treadmill training on axon regeneration directly to those produced by ES, we will evaluate whether the enhancement of axon regeneration produced is similar. Synapse re-formation is a critical part of functional recovery after injury to the PNS, and without intervention, it takes longer than it takes regenerating axons to grow sufficiently to reach the muscles. We will compare the effect of ES and treadmill training on the time course of neuromuscular synapse re-formation in transgenic mice. Because it activates motoneurons naturally via their intrinsic neural circuits, exercise could be a way of enhancing regeneration with less functionally inappropriate reinnervation of muscles than noted with ES. The specificity of reinnervation of four different muscle targets will be compared, using retrograde fluorescent labeling methods, in untreated, electrically stimulated, and treadmill trained mice. Exercise has the potential to ameliorate both of the major issues contributing to poor functional recovery from lesions to the PNS. Its potential for clinical use with low cost and very high benefit is great. This project provides a unique opportunity to provide answers important to questions that will strengthen the basis for such clinical use.